Samay Jain M.D., M.S. is a junior faculty member in the University of Pittsburgh, Department of Neurology Movement Disorders Division since 2006. In 2007, Dr. Jain began participating in the Multidisciplinary Clinical Research Scholars Program with funding through the KL2/K12 mechanism for a proposal entitled, Improving diagnosis and treatment of Parkinson disease with assessments of non-motor features by clinical and physiologic measures. As part of this program, he has completed a Masters of Science in Clinical Research and generated preliminary data for this K23 application. Although this has provided formal training on general clinical research methodology, what the candidate lacks are specific skills necessary to conduct his specialized area of research: electrophysiological measures of autonomic function in Parkinson disease (PD). The six objectives of this five year career development proposal are to: (1) Refine research skills in movement disorders and autonomic function; (2) Acquire skills to gather, analyze and interpret electrophysiological data; (3) Apply successful strategies of geriatric clinical research to recruit and retain an elderly cohort; (4) Develop expertise in pharmacology as it relates to autonomic function and PD; (5) Apply biostatistics for hypothesis testing of longitudinal and complex physiologic data; and (6) Integrate research skills into efficient scientific writing. The primary mentor overseeing all activities is Dr. J. Timothy Greenamyre. The career development plan utilizes resources available with mentors, consultants and coursework in the areas of neurology, physiology, geriatrics, pharmacology and biostatistics. All data and analyses presented here were done in the facilities of mentors and consultants with close supervision and discussion. These resources, which continue to be available for this proposal, include a new, fully equipped physiological laboratory dedicated solely to the candidate's research where training and testing occur; two additional physiological laboratories of mentors available for testing and training, the Pittsburgh Claude D. Pepper Older Americans Independence Center with resources for recruitment and retention of geriatric participants; the Pittsburgh Institute for Neurodegenerative diseases; and the Comprehensive Movement Disorders Center. In addition, education and expertise at the NIH Clinical Center in Bethesda, MD will be available through co-mentor Dr. David S. Goldstein. The immediate goal of the career development plan is to for the PI to achieve independence in conducting autonomic electrophysiological research in PD. The long term goal is to become a leader in clinical research utilizing autonomic measures to develop treatments for non-motor features of PD and monitor PD progression in interventional trials with non-invasive electrophysiological techniques. PD is the second most common neurodegenerative disease affecting over one-million Americans with annual cost of $23 billion. Non-motor features, including autonomic symptoms, occur in 90% of PD patients and account for greater influence on quality of life and healthcare costs than impairment in motor function. Our goal is to develop non-invasive measures that will allow understanding of autonomic physiology in PD. This will reduce the burden of PD by informing diagnostic and treatment strategies. We seek to integrate autonomic physiology, motor features and anti-parkinsonian medications in a model of PD that can be applied to interventional PD trials. This challenges current approaches of PD which rely solely on motor impairment as a measure of disease progression. We apply a novel protocol translating techniques from psychophysiology to non-invasively measure autonomic function in PD in the pupillary, cardiovascular (CV) and gastrointestinal (GI) systems. Our specific aims are to: (1) relate autonomic physiology in the pupillary, GI and CV systems to PD motor severity; (2) identify mechanisms by which dopaminergic medication influence autonomic physiology in PD; and (3) evaluate the extent to which autonomic dysfunction in the pupillary, CV and GI systems in PD is related to progression of Parkinsonism. To accomplish this, we will compare autonomic measures of 60 individuals PD and 60 age and sex-matched controls, 40 PD participants on and off dopaminergic medication, and follow 60 PD and 40 controls every 6 months for 24 months. As PD severity increases we predict a defined sequence of accumulation in autonomic dysfunction across the GI, CV and pupillary systems upon which anti-parkinsonian medications mediate effects via specific sympathetic and parasympathetic pathways. We also expect the rate of change of autonomic function in PD to correlate with the rate of change in severity of Parkinsonian motor signs. Upon completion of this proposal, the candidate will have applied for R01 funding establishing a foundation to become a leader in clinical research with a sustainable plan to apply autonomic electrophysiology to the diagnosis and treatment of PD as well as understanding mechanisms which underlie PD.